MicroRNAs (miRNAs) are single-stranded noncoding RNAs of ˜22 nucleotides. They are a novel class of gene regulators that function by binding to the 3′ untranslated region of target messenger RNAs leading to either suppression of their translation or acceleration of their degradation (Bartel (2004) Cell 116:287; Carthew (2006) Curr. Opin. Genet. Dev. 16:203; He & Hannon (2004) Nat. Rev. Genet. 5:522; Cullen (2004) Mol. Cell. 16:861; Du & Zamore (2005) Development 132:4645). The majority of miRNAs are initially transcribed by RNA polymerase II as primary transcripts (pri-miRNAs) that require subsequent processing to yield a functional mature miRNA (Bartel (2004) supra; Carthew (2006) supra; He & Hannon (2004) supra; Cullen (2004) supra; Du & Zamore (2005) supra). Pri-miRNAs are processed in the nucleus by the RNAse III enzyme Drosha, partnering with DGCR8 (in vertebrates) or Pasha (in invertebrates), and transforming pri-miRNAs into shorter stem-loop-structured, double-stranded RNAs (dsRNAs) called precursor miRNAs (pre-miRNAs) (Denli, et al. (2004) Nature 432:231; Gregory, et al. (2004) Nature 432:235; Lee, et al. (2003) Nature 425:415). Pre-miRNAs are then transported from the nucleus to the cytoplasm and are processed by Dicer into mature miRNAs (Bernstein, et al. (2001) Nature 409:363; Grishok, et al. (2001) Cell 106:23-34; Hutvagner, et al. (2001) Science 293:834; Ketting, et al. (2001) Genes Dev. 15:2654; Yi, et al. (2003) Genes Dev. 17:3011). Mature miRNAs enter the effector complex, called the RNA-induced silencing complex (RISC), to target single-stranded complementary mRNAs for translational repression or mRNA degradation (Hammond (2006) Curr. Opin. Genet. Dev. 16:4-9; Hammond, et al. (2000) Nature 404:293; Hutvagner & Zamore (2002) Science 297:2056; Valencia-Sanchez, et al. (2006) Genes Dev. 20:515; Filipowicz (2005) Cell 122:17-20; Doench & Sharp (2004) Genes Dev. 18:504). It is estimated that miRNAs are involved in the regulation of about 30% of all genes and almost every genetic pathway (Hwang & Mendell (2006) Br. J. Cancer 94:776).
MicroRNAs play important roles in processes as diverse as normal development and cellular homeostasis (Bartel (2004) Cell 116:287-297; Plasterk (2006) Cell 124:877-881). Moreover, strong evidence suggests that they can function as oncogenes or tumor suppressors (Chan, et al. (2005) Cancer Res. 65:6029; Cimmino, et al. (2005) Proc. Natl. Acad. Sci. USA 102:139449; He, et al. (2005) Nature 435:828; Zhang, et al. (2006) Proc. Natl. Acad. Sci. USA 103:9136). For example, human miR-373 and 520C miRNAs have been shown to stimulate cancer cell migration and induce tumor cell invasion in vitro and in vivo. Mechanistically, the migration phenotype of miR-373 and miR-520C is explained by their suppression of CD44 expression. miR-373 and miR-520C inhibit CD44 expression through two sites at the 3′-UTR of CD44. Ectopic expression of CD44 restrains migration induced by miR-373 and miR-520C, while suppression of CD44 expression induces migration and metastasis (Huang, et al. (2008) Nature Cell Biology 10:202). Furthermore, a significant up-regulation of miR-373 expression is observed in clinical breast cancer primary and metastasis samples, wherein miR-373 expression is inversely correlated with CD44 expression in these tumors. While specific miRNA inhibition has been achieved by antisense nucleic acid approaches, effective delivery of such molecules is an issue (Meister, et al. (2004) Mol. Cell. 15:185).